14-24368423-C-G

Position:

• chr14-24368423-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004554.5(NFATC4):​c.83C>G​(p.Ala28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000859 in 1,164,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: NFATC4 NM_004554.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

Genes affected

NFATC4 (HGNC:7778): (nuclear factor of activated T cells 4) This gene encodes a member of the nuclear factor of activated T cells (NFAT) protein family. The encoded protein is part of a DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor stimulation and an inducible nuclear component. NFAT proteins are activated by the calmodulin-dependent phosphatase, calcineurin. The encoded protein plays a role in the inducible expression of cytokine genes in T cells, especially in the induction of interleukin-2 and interleukin-4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

LOC124903291 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112273246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC4	NM_004554.5	c.83C>G	p.Ala28Gly	missense_variant	1/10	ENST00000250373.9
LOC124903291	XR_007064085.1	n.139+824G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC4	ENST00000250373.9	c.83C>G	p.Ala28Gly	missense_variant	1/10	1	NM_004554.5	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.59e-7 AC: 1 AN: 1164518 Hom.: 0 Cov.: 34 AF XY: 0.00000179 AC XY: 1 AN XY: 558282

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.83C>G (p.A28G) alteration is located in exon 1 (coding exon 1) of the NFATC4 gene. This alteration results from a C to G substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0018	.;.;.;.;.;.;.;.;.;T;T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.49	N
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;N;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.070	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.050	B;B;B;B;B;B;B;B;.;.;.;B;.
Vest4		0.18
MutPred		0.19		.;.;.;.;.;.;.;.;Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.32
MPC		0.34
ClinPred		0.11	T
GERP RS		2.6
Varity_R		0.078
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199738451; hg19: chr14-24837629;